Abstract
Bile acids (BAs) can regulate their own metabolism and transport as well as other key aspects of metabolic homeostasis via dedicated (nuclear and G protein-coupled) receptors. Disrupted BA transport and homeostasis results in the development of cholestatic disorders and contributes to a wide range of liver diseases, including nonalcoholic fatty liver disease and hepatocellular and cholangiocellular carcinoma. Furthermore, impaired BA homeostasis can also affect the intestine, contributing to the pathogenesis of irritable bowel syndrome, inflammatory bowel disease, and colorectal and oesophageal cancer. Here, we provide a summary of the role of BAs and their disrupted homeostasis in the development of gastrointestinal and hepatic disorders and present novel insights on how targeting BA pathways might contribute to novel treatment strategies for these disorders.
Key points
-
Bile acid (BA)-activated nuclear receptors maintain BA homeostasis by regulating BA metabolism and transport within the enterohepatic circulation.
-
BAs and their nuclear and G protein-coupled receptors also control lipid and/or glucose and energy homeostasis, inflammation and fibrosis as well as cell proliferation and other processes affecting carcinogenic risk.
-
BAs exert immunomodulatory effects via modulation of cytokine secretion from hepatocytes and immune cells.
-
Targeting BA receptors and transporters pharmacologically is a rapidly evolving field of therapeutic opportunities for liver and gastrointestinal disorders.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Schaap, F. G., Trauner, M. & Jansen, P. L. Bile acid receptors as targets for drug development. Nat. Rev. Gastroenterol. Hepatol. 11, 55–67 (2014).
Hofmann, A. F. Biliary secretion and excretion in health and disease: current concepts. Ann. Hepatol. 6, 15–27 (2007).
Makishima, M. et al. Identification of a nuclear receptor for bile acids. Science 284, 1362–1365 (1999).
Parks, D. J. et al. Bile acids: natural ligands for an orphan nuclear receptor. Science 284, 1365–1368 (1999).
Wang, H., Chen, J., Hollister, K., Sowers, L. C. & Forman, B. M. Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. Mol. Cell 3, 543–553 (1999).
Li, T. & Chiang, J. Y. Nuclear receptors in bile acid metabolism. Drug Metab. Rev. 45, 145–155 (2013).
Halilbasic, E., Fuchs, C., Traussnigg, S. & Trauner, M. Farnesoid X receptor agonists and other bile acid signaling strategies for treatment of liver disease. Dig. Dis. 34, 580–588 (2016).
Perino, A. et al. TGR5 reduces macrophage migration through mTOR-induced C/EBPbeta differential translation. J. Clin. Invest. 124, 5424–5436 (2014).
Yoneno, K. et al. TGR5 signalling inhibits the production of pro-inflammatory cytokines by in vitro differentiated inflammatory and intestinal macrophages in Crohn’s disease. Immunology 139, 19–29 (2013).
Watanabe, M. et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 439, 484–489 (2006).
Inagaki, T. et al. Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab. 2, 217–225 (2005).
Trabelsi, M. S. et al. Farnesoid X receptor inhibits glucagon-like peptide-1 production by enteroendocrine L cells. Nat. Commun. 6, 7629 (2015).
Ducastel, S. et al. The nuclear receptor FXR inhibits glucagon-like peptide-1 secretion in response to microbiota-derived short-chain fatty acids. Sci. Rep. 10, 174 (2020).
Chiang, J. Y. Bile acid metabolism and signaling. Compr. Physiol. 3, 1191–1212 (2013).
Arab, J. P., Karpen, S. J., Dawson, P. A., Arrese, M. & Trauner, M. Bile acids and nonalcoholic fatty liver disease: Molecular insights and therapeutic perspectives. Hepatology 65, 350–362 (2017).
Ishibashi, S., Schwarz, M., Frykman, P. K., Herz, J. & Russell, D. W. Disruption of cholesterol 7alpha-hydroxylase gene in mice. I. Postnatal lethality reversed by bile acid and vitamin supplementation. J. Biol. Chem. 271, 18017–18023 (1996).
Schwarz, M. et al. Disruption of cholesterol 7alpha-hydroxylase gene in mice. II. Bile acid deficiency is overcome by induction of oxysterol 7alpha-hydroxylase. J. Biol. Chem. 271, 18024–18031 (1996).
Chen, W. & Chiang, J. Y. Regulation of human sterol 27-hydroxylase gene (CYP27A1) by bile acids and hepatocyte nuclear factor 4alpha (HNF4alpha). Gene 313, 71–82 (2003).
Takahashi, S. et al. Cyp2c70 is responsible for the species difference in bile acid metabolism between mice and humans. J. Lipid Res. 57, 2130–2137 (2016).
Monte, M. J., Marin, J. J., Antelo, A. & Vazquez-Tato, J. Bile acids: chemistry, physiology, and pathophysiology. World J. Gastroenterol. 15, 804–816 (2009).
Dawson, P. A., Lan, T. & Rao, A. Bile acid transporters. J. Lipid Res. 50, 2340–2357 (2009).
Trauner, M. & Boyer, J. L. Bile salt transporters: molecular characterization, function, and regulation. Physiol. Rev. 83, 633–671 (2003).
Boyer, J. L. Bile formation and secretion. Compr. Physiol. 3, 1035–1078 (2013).
Wagner, M., Zollner, G. & Trauner, M. New molecular insights into the mechanisms of cholestasis. J. Hepatol. 51, 565–580 (2009).
Thomas, C., Pellicciari, R., Pruzanski, M., Auwerx, J. & Schoonjans, K. Targeting bile-acid signalling for metabolic diseases. Nat. Rev. Drug Discov. 7, 678–693 (2008).
Chiang, J. Y. Bile acids: regulation of synthesis. J. Lipid Res. 50, 1955–1966 (2009).
Lu, T. T. et al. Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. Mol. Cell 6, 507–515 (2000).
Miao, J. et al. Bile acid signaling pathways increase stability of small heterodimer partner (SHP) by inhibiting ubiquitin-proteasomal degradation. Genes Dev. 23, 986–996 (2009).
Byun, S. et al. Postprandial FGF19-induced phosphorylation by Src is critical for FXR function in bile acid homeostasis. Nat. Commun. 9, 2590 (2018).
Modica, S., Gadaleta, R. M. & Moschetta, A. Deciphering the nuclear bile acid receptor FXR paradigm. Nucl. Recept. Signal. 8, e005 (2010).
Angelin, B., Einarsson, K., Hellstrom, K. & Leijd, B. Effects of cholestyramine and chenodeoxycholic acid on the metabolism of endogenous triglyceride in hyperlipoproteinemia. J. Lipid Res. 19, 1017–1024 (1978).
Stayrook, K. R. et al. Regulation of carbohydrate metabolism by the farnesoid X receptor. Endocrinology 146, 984–991 (2005).
Park, M. J. et al. Transcriptional repression of the gluconeogenic gene PEPCK by the orphan nuclear receptor SHP through inhibitory interaction with C/EBPalpha. Biochem. J. 402, 567–574 (2007).
Yamagata, K. et al. Bile acids regulate gluconeogenic gene expression via small heterodimer partner-mediated repression of hepatocyte nuclear factor 4 and Foxo1. J. Biol. Chem. 279, 23158–23165 (2004).
Borgius, L. J., Steffensen, K. R., Gustafsson, J. A. & Treuter, E. Glucocorticoid signaling is perturbed by the atypical orphan receptor and corepressor SHP. J. Biol. Chem. 277, 49761–49766 (2002).
Cariou, B. et al. The farnesoid X receptor modulates adiposity and peripheral insulin sensitivity in mice. J. Biol. Chem. 281, 11039–11049 (2006).
Cariou, B. et al. Transient impairment of the adaptive response to fasting in FXR-deficient mice. FEBS Lett. 579, 4076–4080 (2005).
Zhang, Y. et al. Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice. Proc. Natl Acad. Sci. USA 103, 1006–1011 (2006).
Han, S. I. et al. Bile acids enhance the activity of the insulin receptor and glycogen synthase in primary rodent hepatocytes. Hepatology 39, 456–463 (2004).
Fang, Y. et al. Bile acids induce mitochondrial ROS, which promote activation of receptor tyrosine kinases and signaling pathways in rat hepatocytes. Hepatology 40, 961–971 (2004).
Kir, S. et al. FGF19 as a postprandial, insulin-independent activator of hepatic protein and glycogen synthesis. Science 331, 1621–1624 (2011).
Keitel, V. & Haussinger, D. Role of TGR5 (GPBAR1) in Liver Disease. Semin. Liver Dis. 38, 333–339 (2018).
Thomas, C. et al. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab. 10, 167–177 (2009).
Katsuma, S., Hirasawa, A. & Tsujimoto, G. Bile acids promote glucagon-like peptide-1 secretion through TGR5 in a murine enteroendocrine cell line STC-1. Biochem. Biophys. Res. Commun. 329, 386–390 (2005).
Lasalle, M. et al. Topical intestinal aminoimidazole agonists of G-protein-coupled bile acid receptor 1 promote glucagon like peptide-1 secretion and improve glucose tolerance. J. Med. Chem. 60, 4185–4211 (2017).
Cao, H. et al. Intestinally-targeted TGR5 agonists equipped with quaternary ammonium have an improved hypoglycemic effect and reduced gallbladder filling effect. Sci. Rep. 6, 28676 (2016).
Kuhre, R. E. et al. Bile acids are important direct and indirect regulators of the secretion of appetite- and metabolism-regulating hormones from the gut and pancreas. Mol. Metab. 11, 84–95 (2018).
Thomas, C., Auwerx, J. & Schoonjans, K. Bile acids and the membrane bile acid receptor TGR5–connecting nutrition and metabolism. Thyroid 18, 167–174 (2008).
Jansen, P. L. et al. The ascending pathophysiology of cholestatic liver disease. Hepatology 65, 722–738 (2017).
Woolbright, B. L., McGill, M. R., Yan, H. & Jaeschke, H. Bile acid-induced toxicity in HepaRG cells recapitulates the response in primary human hepatocytes. Basic Clin. Pharmacol. Toxicol. 118, 160–167 (2016).
Woolbright, B. L. et al. Bile acid-induced necrosis in primary human hepatocytes and in patients with obstructive cholestasis. Toxicol. Appl. Pharmacol. 283, 168–177 (2015).
Galle, P. R., Theilmann, L., Raedsch, R., Otto, G. & Stiehl, A. Ursodeoxycholate reduces hepatotoxicity of bile salts in primary human hepatocytes. Hepatology 12, 486–491 (1990).
Spivey, J. R., Bronk, S. F. & Gores, G. J. Glycochenodeoxycholate-induced lethal hepatocellular injury in rat hepatocytes. Role of ATP depletion and cytosolic free calcium. J. Clin. Invest. 92, 17–24 (1993).
Song, P., Zhang, Y. & Klaassen, C. D. Dose-response of five bile acids on serum and liver bile acid concentrations and hepatotoxicty in mice. Toxicol. Sci. 123, 359–367 (2011).
Hofmann, A. F. & Roda, A. Physicochemical properties of bile acids and their relationship to biological properties: an overview of the problem. J. Lipid Res. 25, 1477–1489 (1984).
Wahlstrom, A., Sayin, S. I., Marschall, H. U. & Backhed, F. Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism. Cell Metab. 24, 41–50 (2016).
Miyake, J. H., Wang, S. L. & Davis, R. A. Bile acid induction of cytokine expression by macrophages correlates with repression of hepatic cholesterol 7alpha-hydroxylase. J. Biol. Chem. 275, 21805–21808 (2000).
Sato, K. et al. Pathogenesis of Kupffer cells in cholestatic liver injury. Am. J. Pathol. 186, 2238–2247 (2016).
Allen, K., Jaeschke, H. & Copple, B. L. Bile acids induce inflammatory genes in hepatocytes: a novel mechanism of inflammation during obstructive cholestasis. Am. J. Pathol. 178, 175–186 (2011).
Allen, K., Kim, N. D., Moon, J. O. & Copple, B. L. Upregulation of early growth response factor-1 by bile acids requires mitogen-activated protein kinase signaling. Toxicol. Appl. Pharmacol. 243, 63–67 (2010).
O’Brien, K. M. et al. IL-17A synergistically enhances bile acid-induced inflammation during obstructive cholestasis. Am. J. Pathol. 183, 1498–1507 (2013).
Meng, F. et al. Interleukin-17 signaling in inflammatory, Kupffer cells, and hepatic stellate cells exacerbates liver fibrosis in mice. Gastroenterology 143, 765–776.e3 (2012).
Bleier, J. I. et al. Biliary obstruction selectively expands and activates liver myeloid dendritic cells. J. Immunol. 176, 7189–7195 (2006).
Connolly, M. K. et al. In liver fibrosis, dendritic cells govern hepatic inflammation in mice via TNF-alpha. J. Clin. Invest. 119, 3213–3225 (2009).
Rahman, A. H. & Aloman, C. Dendritic cells and liver fibrosis. Biochim. Biophys. Acta 1832, 998–1004 (2013).
Carambia, A. et al. TGF-beta-dependent induction of CD4+CD25+Foxp3+ Tregs by liver sinusoidal endothelial cells. J. Hepatol. 61, 594–599 (2014).
Licata, L. A. et al. Biliary obstruction results in PD-1-dependent liver T cell dysfunction and acute inflammation mediated by Th17 cells and neutrophils. J. Leukoc. Biol. 94, 813–823 (2013).
Alimov, I. et al. Bile acid analogues are activators of pyrin inflammasome. J. Biol. Chem. 294, 3359–3366 (2019).
Hao, H. et al. Farnesoid X receptor regulation of the NLRP3 inflammasome underlies cholestasis-associated sepsis. Cell Metab. 25, 856–867.e5 (2017).
Wang, Y. D. et al. Farnesoid X receptor antagonizes nuclear factor kappaB in hepatic inflammatory response. Hepatology 48, 1632–1643 (2008).
Wagner, M., Zollner, G. & Trauner, M. Nuclear bile acid receptor farnesoid X receptor meets nuclear factor-kappaB: new insights into hepatic inflammation. Hepatology 48, 1383–1386 (2008).
Vavassori, P., Mencarelli, A., Renga, B., Distrutti, E. & Fiorucci, S. The bile acid receptor FXR is a modulator of intestinal innate immunity. J. Immunol. 183, 6251–6261 (2009).
Mencarelli, A. et al. The bile acid sensor farnesoid X receptor is a modulator of liver immunity in a rodent model of acute hepatitis. J. Immunol. 183, 6657–6666 (2009).
Campbell, C. et al. FXR mediates T cell-intrinsic responses to reduced feeding during infection. Proc. Natl Acad. Sci. USA 117, 33446–33454 (2020).
Renga, B. et al. The bile acid sensor FXR is required for immune-regulatory activities of TLR-9 in intestinal inflammation. PLoS One 8, e54472 (2013).
Wildenberg, M. E. & van den Brink, G. R. FXR activation inhibits inflammation and preserves the intestinal barrier in IBD. Gut 60, 432–433 (2011).
Gadaleta, R. M. et al. Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease. Gut 60, 463–472 (2011).
Massafra, V. et al. Splenic dendritic cell involvement in FXR-mediated amelioration of DSS colitis. Biochim. Biophys. Acta 1862, 166–173 (2016).
Fiorucci, S., Biagioli, M., Zampella, A. & Distrutti, E. Bile acids activated receptors regulate innate immunity. Front. Immunol. 9, 1853 (2018).
Pizzagalli, M. D., Bensimon, A. & Superti-Furga, G. A guide to plasma membrane solute carrier proteins. FEBS J. 288, 2784–2835 (2021).
Skazik, C. et al. Differential expression of influx and efflux transport proteins in human antigen presenting cells. Exp. Dermatol. 17, 739–747 (2008).
Maruyama, T. et al. Identification of membrane-type receptor for bile acids (M-BAR). Biochem. Biophys. Res. Commun. 298, 714–719 (2002).
Keitel, V., Donner, M., Winandy, S., Kubitz, R. & Haussinger, D. Expression and function of the bile acid receptor TGR5 in Kupffer cells. Biochem. Biophys. Res. Commun. 372, 78–84 (2008).
Pols, T. W. et al. TGR5 activation inhibits atherosclerosis by reducing macrophage inflammation and lipid loading. Cell Metab. 14, 747–757 (2011).
Fiorucci, S. et al. Counter-regulatory role of bile acid activated receptors in immunity and inflammation. Curr. Mol. Med. 10, 579–595 (2010).
Ichikawa, R. et al. Bile acids induce monocyte differentiation toward interleukin-12 hypo-producing dendritic cells via a TGR5-dependent pathway. Immunology 136, 153–162 (2012).
Chen, M. L., Takeda, K. & Sundrud, M. S. Emerging roles of bile acids in mucosal immunity and inflammation. Mucosal Immunol. 12, 851–861 (2019).
Pean, N. et al. The receptor TGR5 protects the liver from bile acid overload during liver regeneration in mice. Hepatology 58, 1451–1460 (2013).
Liston, A. & Whyte, C. E. Bile acids mediate signaling between microbiome and the immune system. Immunol. Cell Biol. 98, 349–350 (2020).
Campbell, C. et al. Bacterial metabolism of bile acids promotes generation of peripheral regulatory T cells. Nature 581, 475–479 (2020).
Song, X. et al. Microbial bile acid metabolites modulate gut RORgamma+ regulatory T cell homeostasis. Nature 577, 410–415 (2020).
Hang, S. et al. Bile acid metabolites control TH17 and Treg cell differentiation. Nature 576, 143–148 (2019).
Trauner, M., Meier, P. J. & Boyer, J. L. Molecular pathogenesis of cholestasis. N. Engl. J. Med. 339, 1217–1227 (1998).
Zollner, G., Marschall, H. U., Wagner, M. & Trauner, M. Role of nuclear receptors in the adaptive response to bile acids and cholestasis: pathogenetic and therapeutic considerations. Mol. Pharm. 3, 231–251 (2006).
Zollner, G. et al. Coordinated induction of bile acid detoxification and alternative elimination in mice: role of FXR-regulated organic solute transporter-alpha/beta in the adaptive response to bile acids. Am. J. Physiol. Gastrointest. Liver Physiol. 290, G923–G932 (2006).
Zollner, G. et al. Role of nuclear bile acid receptor, FXR, in adaptive ABC transporter regulation by cholic and ursodeoxycholic acid in mouse liver, kidney and intestine. J. Hepatol. 39, 480–488 (2003).
Zollner, G. et al. Adaptive changes in hepatobiliary transporter expression in primary biliary cirrhosis. J. Hepatol. 38, 717–727 (2003).
Trauner, M., Wagner, M., Fickert, P. & Zollner, G. Molecular regulation of hepatobiliary transport systems: clinical implications for understanding and treating cholestasis. J. Clin. Gastroenterol. 39 (Suppl. 2), S111–S124 (2005).
Kim, M. S., Shigenaga, J., Moser, A., Feingold, K. & Grunfeld, C. Repression of farnesoid X receptor during the acute phase response. J. Biol. Chem. 278, 8988–8995 (2003).
Ghose, R., Zimmerman, T. L., Thevananther, S. & Karpen, S. J. Endotoxin leads to rapid subcellular re-localization of hepatic RXRalpha: A novel mechanism for reduced hepatic gene expression in inflammation. Nucl. Recept. 2, 4 (2004).
Gomez-Ospina, N. et al. Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis. Nat. Commun. 7, 10713 (2016).
Li, Y., Jadhav, K. & Zhang, Y. Bile acid receptors in non-alcoholic fatty liver disease. Biochem. Pharmacol. 86, 1517–1524 (2013).
Yuan, L. & Bambha, K. Bile acid receptors and nonalcoholic fatty liver disease. World J. Hepatol. 7, 2811–2818 (2015).
Ferslew, B. C. et al. Altered bile acid metabolome in patients with nonalcoholic steatohepatitis. Dig. Dis. Sci. 60, 3318–3328 (2015).
Mouzaki, M. et al. Bile acids and dysbiosis in non-alcoholic fatty liver disease. PLoS One 11, e0151829 (2016).
Jiao, N. et al. Suppressed hepatic bile acid signalling despite elevated production of primary and secondary bile acids in NAFLD. Gut 67, 1881–1891 (2018).
Gottlieb, A. & Canbay, A. Why bile acids are so important in non-alcoholic fatty liver disease (NAFLD) progression. Cells 8, 1358 (2019).
Puri, P. et al. The presence and severity of nonalcoholic steatohepatitis is associated with specific changes in circulating bile acids. Hepatology 67, 534–548 (2018).
Jahn, D. & Geier, A. Bile acids in nonalcoholic steatohepatitis: pathophysiological driving force or innocent bystanders? Hepatology 67, 464–466 (2018).
Bechmann, L. P. et al. Free fatty acids repress small heterodimer partner (SHP) activation and adiponectin counteracts bile acid-induced liver injury in superobese patients with nonalcoholic steatohepatitis. Hepatology 57, 1394–1406 (2013).
Grzych, G. et al. NASH-related increases in plasma bile acid levels depend on insulin resistance. JHEP Rep. 3, 100222 (2021).
Haeusler, R. A., Astiarraga, B., Camastra, S., Accili, D. & Ferrannini, E. Human insulin resistance is associated with increased plasma levels of 12alpha-hydroxylated bile acids. Diabetes 62, 4184–4191 (2013).
Legry, V. et al. Bile acid alterations are associated with insulin resistance, but not with NASH, in obese subjects. J. Clin. Endocrinol. Metab. 102, 3783–3794 (2017).
Yoshimoto, S. et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 499, 97–101 (2013).
Chen, L. et al. Genetic and microbial associations to plasma and fecal bile acids in obesity relate to plasma lipids and liver fat content. Cell Rep. 33, 108212 (2020).
Canet, M. J. et al. Altered regulation of hepatic efflux transporters disrupts acetaminophen disposition in pediatric nonalcoholic steatohepatitis. Drug. Metab. Dispos. 43, 829–835 (2015).
Schreuder, T. C. et al. The hepatic response to FGF19 is impaired in patients with nonalcoholic fatty liver disease and insulin resistance. Am. J. Physiol. Gastrointest. Liver Physiol. 298, G440–G445 (2010).
Acalovschi, M. et al. Common variants of ABCB4 and ABCB11 and plasma lipid levels: a study in sib pairs with gallstones, and controls. Lipids 44, 521–526 (2009).
Pizarro, M. et al. Bile secretory function in the obese Zucker rat: evidence of cholestasis and altered canalicular transport function. Gut 53, 1837–1843 (2004).
Baptissart, M. et al. Bile acids: from digestion to cancers. Biochimie 95, 504–517 (2013).
Leung, C. et al. Characteristics of hepatocellular carcinoma in cirrhotic and non-cirrhotic non-alcoholic fatty liver disease. World J. Gastroenterol. 21, 1189–1196 (2015).
Huang, W. et al. Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration. Science 312, 233–236 (2006).
Yang, F. et al. Spontaneous development of liver tumors in the absence of the bile acid receptor farnesoid X receptor. Cancer Res. 67, 863–867 (2007).
Kim, I. et al. Spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice. Carcinogenesis 28, 940–946 (2007).
Wolfe, A. et al. Increased activation of the Wnt/beta-catenin pathway in spontaneous hepatocellular carcinoma observed in farnesoid X receptor knockout mice. J. Pharmacol. Exp. Ther. 338, 12–21 (2011).
Pikarsky, E. et al. NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature 431, 461–466 (2004).
Wang, Y. D., Chen, W. D., Yu, D., Forman, B. M. & Huang, W. The G-protein-coupled bile acid receptor, Gpbar1 (TGR5), negatively regulates hepatic inflammatory response through antagonizing nuclear factor kappa light-chain enhancer of activated B cells (NF-kappaB) in mice. Hepatology 54, 1421–1432 (2011).
Dent, P. et al. Conjugated bile acids promote ERK1/2 and AKT activation via a pertussis toxin-sensitive mechanism in murine and human hepatocytes. Hepatology 42, 1291–1299 (2005).
Magee, N. & Zhang, Y. Role of early growth response 1 in liver metabolism and liver cancer. Hepatoma Res. 3, 268–277 (2017).
Lanaya, H. et al. EGFR has a tumour-promoting role in liver macrophages during hepatocellular carcinoma formation. Nat. Cell Biol. 16, 972–977 (2014).
Holt, J. A. et al. Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis. Genes Dev. 17, 1581–1591 (2003).
Nicholes, K. et al. A mouse model of hepatocellular carcinoma: ectopic expression of fibroblast growth factor 19 in skeletal muscle of transgenic mice. Am. J. Pathol. 160, 2295–2307 (2002).
French, D. M. et al. Targeting FGFR4 inhibits hepatocellular carcinoma in preclinical mouse models. PLoS One 7, e36713 (2012).
Desnoyers, L. R. et al. Targeting FGF19 inhibits tumor growth in colon cancer xenograft and FGF19 transgenic hepatocellular carcinoma models. Oncogene 27, 85–97 (2008).
Ho, H. K. et al. Fibroblast growth factor receptor 4 regulates proliferation, anti-apoptosis and alpha-fetoprotein secretion during hepatocellular carcinoma progression and represents a potential target for therapeutic intervention. J. Hepatol. 50, 118–127 (2009).
Gauglhofer, C. et al. Up-regulation of the fibroblast growth factor 8 subfamily in human hepatocellular carcinoma for cell survival and neoangiogenesis. Hepatology 53, 854–864 (2011).
Heinzle, C. et al. Is fibroblast growth factor receptor 4 a suitable target of cancer therapy? Curr. Pharm. Des. 20, 2881–2898 (2014).
Raja, A., Park, I., Haq, F. & Ahn, S. M. FGF19-FGFR4 signaling in hepatocellular carcinoma. Cells 8, 536 (2019).
Sawey, E. T. et al. Identification of a therapeutic strategy targeting amplified FGF19 in liver cancer by oncogenomic screening. Cancer Cell 19, 347–358 (2011).
Zhou, M. et al. Mouse species-specific control of hepatocarcinogenesis and metabolism by FGF19/FGF15. J. Hepatol. 66, 1182–1192 (2017).
Zhou, M. et al. Separating tumorigenicity from bile acid regulatory activity for endocrine hormone FGF19. Cancer Res. 74, 3306–3316 (2014).
Friedman, S. L. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol. Rev. 88, 125–172 (2008).
Sun, B. & Karin, M. Obesity, inflammation, and liver cancer. J. Hepatol. 56, 704–713 (2012).
Song, J. et al. Cholangiocarcinoma in patients with primary sclerosing cholangitis (PSC): a comprehensive review. Clin. Rev. Allergy Immunol. 58, 134–149 (2020).
Cannito, S. et al. Fibroinflammatory liver injuries as preneoplastic condition in cholangiopathies. Int. J. Mol. Sci. 19, 3875 (2018).
Lozano, E. et al. Cocarcinogenic effects of intrahepatic bile acid accumulation in cholangiocarcinoma development. Mol. Cancer Res. 12, 91–100 (2014).
Werneburg, N. W., Yoon, J. H., Higuchi, H. & Gores, G. J. Bile acids activate EGF receptor via a TGF-alpha-dependent mechanism in human cholangiocyte cell lines. Am. J. Physiol. Gastrointest. Liver Physiol. 285, G31–G36 (2003).
Liu, R. et al. Conjugated bile acids promote cholangiocarcinoma cell invasive growth through activation of sphingosine 1-phosphate receptor 2. Hepatology 60, 908–918 (2014).
Keitel, V., Reich, M. & Haussinger, D. TGR5: pathogenetic role and/or therapeutic target in fibrosing cholangitis? Clin. Rev. Allergy Immunol. 48, 218–225 (2015).
Reich, M. et al. TGR5 is essential for bile acid-dependent cholangiocyte proliferation in vivo and in vitro. Gut 65, 487–501 (2016).
Dai, J. et al. Impact of bile acids on the growth of human cholangiocarcinoma via FXR. J. Hematol. Oncol. 4, 41 (2011).
Lozano, E. et al. Enhanced antitumour drug delivery to cholangiocarcinoma through the apical sodium-dependent bile acid transporter (ASBT). J. Control. Rel. 216, 93–102 (2015).
Horvatits, T., Drolz, A., Trauner, M. & Fuhrmann, V. Liver injury and failure in critical illness. Hepatology 70, 2204–2215 (2019).
Trauner, M., Fickert, P. & Stauber, R. E. Inflammation-induced cholestasis. J. Gastroenterol. Hepatol. 14, 946–959 (1999).
de Tymowski, C. et al. Contributing factors and outcomes of burn-associated cholestasis. J. Hepatol. 71, 563–572 (2019).
Geier, A., Fickert, P. & Trauner, M. Mechanisms of disease: mechanisms and clinical implications of cholestasis in sepsis. Nat. Clin. Pract. Gastroenterol. Hepatol. 3, 574–585 (2006).
Recknagel, P. et al. Liver dysfunction and phosphatidylinositol-3-kinase signalling in early sepsis: experimental studies in rodent models of peritonitis. PLoS Med. 9, e1001338 (2012).
Trauner, M., Meier, P. J. & Boyer, J. L. Molecular regulation of hepatocellular transport systems in cholestasis. J. Hepatol. 31, 165–178 (1999).
Denson, L. A., Karpen, S. J., Bogue, C. W. & Jacobs, H. C. Divergent homeobox gene hex regulates promoter of the Na+-dependent bile acid cotransporter. Am. J. Physiol. Gastrointest. Liver Physiol. 279, G347–G355 (2000).
Karpen, S. J. et al. Multiple factors regulate the rat liver basolateral sodium-dependent bile acid cotransporter gene promoter. J. Biol. Chem. 271, 15211–15221 (1996).
Trauner, M., Arrese, M., Lee, H., Boyer, J. L. & Karpen, S. J. Endotoxin downregulates rat hepatic ntcp gene expression via decreased activity of critical transcription factors. J. Clin. Invest. 101, 2092–2100 (1998).
Zollner, G. et al. Induction of short heterodimer partner 1 precedes downregulation of Ntcp in bile duct-ligated mice. Am. J. Physiol. Gastrointest. Liver Physiol. 282, G184–G191 (2002).
Geier, A. et al. Cytokine-dependent regulation of hepatic organic anion transporter gene transactivators in mouse liver. Am. J. Physiol. Gastrointest. Liver Physiol. 289, G831–G841 (2005).
Lund, M., Kang, L., Tygstrup, N., Wolkoff, A. W. & Ott, P. Effects of LPS on transport of indocyanine green and alanine uptake in perfused rat liver. Am. J. Physiol. 277, G91–G100 (1999).
Cherrington, N. J., Slitt, A. L., Li, N. & Klaassen, C. D. Lipopolysaccharide-mediated regulation of hepatic transporter mRNA levels in rats. Drug Metab. Dispos. 32, 734–741 (2004).
Zollner, G. et al. Hepatobiliary transporter expression in percutaneous liver biopsies of patients with cholestatic liver diseases. Hepatology 33, 633–646 (2001).
Trauner, M. et al. The rat canalicular conjugate export pump (Mrp2) is down-regulated in intrahepatic and obstructive cholestasis. Gastroenterology 113, 255–264 (1997).
Denson, L. A. et al. Interleukin-1beta suppresses retinoid transactivation of two hepatic transporter genes involved in bile formation. J. Biol. Chem. 275, 8835–8843 (2000).
Jansen, P. L. & Muller, M. Early events in sepsis-associated cholestasis. Gastroenterology 116, 486–488 (1999).
Haussinger, D., Schmitt, M., Weiergraber, O. & Kubitz, R. Short-term regulation of canalicular transport. Semin. Liver Dis. 20, 307–321 (2000).
Kuhlkamp, T., Keitel, V., Helmer, A., Haussinger, D. & Kubitz, R. Degradation of the sodium taurocholate cotransporting polypeptide (NTCP) by the ubiquitin-proteasome system. Biol. Chem. 386, 1065–1074 (2005).
Jenniskens, M., Langouche, L., Vanwijngaerden, Y. M., Mesotten, D. & Van den Berghe, G. Cholestatic liver (dys)function during sepsis and other critical illnesses. Intensive Care Med. 42, 16–27 (2016).
Strazzabosco, M., Fabris, L. & Spirli, C. Pathophysiology of cholangiopathies. J. Clin. Gastroenterol. 39 (Suppl. 2), S90–S102 (2005).
Booth, A. L., Merwat, S. N., Merwat, S. K. & Stevenson, H. L. Cholangitis lenta: what hepatologists need to know. Clin. Liver Dis. 15, 236–238 (2020).
Spirli, C. et al. Proinflammatory cytokines inhibit secretion in rat bile duct epithelium. Gastroenterology 121, 156–169 (2001).
Spirli, C. et al. Cytokine-stimulated nitric oxide production inhibits adenylyl cyclase and cAMP-dependent secretion in cholangiocytes. Gastroenterology 124, 737–753 (2003).
Fickert, P. et al. Ursodeoxycholic acid aggravates bile infarcts in bile duct-ligated and Mdr2 knockout mice via disruption of cholangioles. Gastroenterology 123, 1238–1251 (2002).
Li, T. & Chiang, J. Y. Bile acid signaling in metabolic disease and drug therapy. Pharmacol. Rev. 66, 948–983 (2014).
Natividad, J. M. et al. Bilophila wadsworthia aggravates high fat diet induced metabolic dysfunctions in mice. Nat. Commun. 9, 2802 (2018).
Devkota, S. et al. Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10-/- mice. Nature 487, 104–108 (2012).
Devkota, S. & Chang, E. B. Interactions between diet, bile acid metabolism, gut microbiota, and inflammatory bowel diseases. Dig. Dis. 33, 351–356 (2015).
Gadaleta, R. M. et al. Activation of bile salt nuclear receptor FXR is repressed by pro-inflammatory cytokines activating NF-kappaB signaling in the intestine. Biochim. Biophys. Acta 1812, 851–858 (2011).
Nijmeijer, R. M. et al. Farnesoid X receptor (FXR) activation and FXR genetic variation in inflammatory bowel disease. PLoS One 6, e23745 (2011).
Attinkara, R. et al. Association of genetic variation in the NR1H4 gene, encoding the nuclear bile acid receptor FXR, with inflammatory bowel disease. BMC Res. Notes 5, 461 (2012).
van Schaik, F. D. et al. Pharmacological activation of the bile acid nuclear farnesoid X receptor is feasible in patients with quiescent Crohn’s colitis. PLoS One 7, e49706 (2012).
Cipriani, S. et al. The bile acid receptor GPBAR-1 (TGR5) modulates integrity of intestinal barrier and immune response to experimental colitis. PLoS One 6, e25637 (2011).
Biagioli, M. et al. The bile acid receptor GPBAR1 regulates the M1/M2 phenotype of intestinal macrophages and activation of GPBAR1 rescues mice from murine colitis. J. Immunol. 199, 718–733 (2017).
Payne, C. M., Bernstein, C., Dvorak, K. & Bernstein, H. Hydrophobic bile acids, genomic instability, Darwinian selection, and colon carcinogenesis. Clin. Exp. Gastroenterol. 1, 19–47 (2008).
Ochsenkuhn, T. et al. Colonic mucosal proliferation is related to serum deoxycholic acid levels. Cancer 85, 1664–1669 (1999).
Bernstein, H., Bernstein, C., Payne, C. M. & Dvorak, K. Bile acids as endogenous etiologic agents in gastrointestinal cancer. World J. Gastroenterol. 15, 3329–3340 (2009).
Baek, M. K. et al. Lithocholic acid upregulates uPAR and cell invasiveness via MAPK and AP-1 signaling in colon cancer cells. Cancer Lett. 290, 123–128 (2010).
Nguyen, T. T. et al. Lithocholic acid stimulates IL-8 expression in human colorectal cancer cells via activation of Erk1/2 MAPK and suppression of STAT3 activity. J. Cell Biochem. 118, 2958–2967 (2017).
Lee, H. Y., Crawley, S., Hokari, R., Kwon, S. & Kim, Y. S. Bile acid regulates MUC2 transcription in colon cancer cells via positive EGFR/PKC/Ras/ERK/CREB, PI3K/Akt/IkappaB/NF-kappaB and p38/MSK1/CREB pathways and negative JNK/c-Jun/AP-1 pathway. Int. J. Oncol. 36, 941–953 (2010).
Arvind, P. et al. Lithocholic acid inhibits the expression of HLA class I genes in colon adenocarcinoma cells. Differential effect on HLA-A, -B and -C loci. Mol. Immunol. 31, 607–614 (1994).
Lax, S. et al. Expression of the nuclear bile acid receptor/farnesoid X receptor is reduced in human colon carcinoma compared to nonneoplastic mucosa independent from site and may be associated with adverse prognosis. Int. J. Cancer 130, 2232–2239 (2012).
Smith, D. L., Keshavan, P., Avissar, U., Ahmed, K. & Zucker, S. D. Sodium taurocholate inhibits intestinal adenoma formation in APCMin/+ mice, potentially through activation of the farnesoid X receptor. Carcinogenesis 31, 1100–1109 (2010).
Peng, Z., Raufman, J. P. & Xie, G. Src-mediated cross-talk between farnesoid X and epidermal growth factor receptors inhibits human intestinal cell proliferation and tumorigenesis. PLoS One 7, e48461 (2012).
Nguyen, T. T., Ung, T. T., Kim, N. H. & Jung, Y. D. Role of bile acids in colon carcinogenesis. World J. Clin. Cases 6, 577–588 (2018).
Lindstrom, L. et al. High dose ursodeoxycholic acid in primary sclerosing cholangitis does not prevent colorectal neoplasia. Aliment. Pharmacol. Ther. 35, 451–457 (2012).
Singh, S., Khanna, S., Pardi, D. S., Loftus, E. V. Jr & Talwalkar, J. A. Effect of ursodeoxycholic acid use on the risk of colorectal neoplasia in patients with primary sclerosing cholangitis and inflammatory bowel disease: a systematic review and meta-analysis. Inflamm. Bowel Dis. 19, 1631–1638 (2013).
Hansen, J. D. et al. Ursodiol and colorectal cancer or dysplasia risk in primary sclerosing cholangitis and inflammatory bowel disease: a meta-analysis. Dig. Dis. Sci. 58, 3079–3087 (2013).
Nehra, D., Howell, P., Williams, C. P., Pye, J. K. & Beynon, J. Toxic bile acids in gastro-oesophageal reflux disease: influence of gastric acidity. Gut 44, 598–602 (1999).
Menges, M., Muller, M. & Zeitz, M. Increased acid and bile reflux in Barrett’s esophagus compared to reflux esophagitis, and effect of proton pump inhibitor therapy. Am. J. Gastroenterol. 96, 331–337 (2001).
Vaezi, M. F., Singh, S. & Richter, J. E. Role of acid and duodenogastric reflux in esophageal mucosal injury: a review of animal and human studies. Gastroenterology 108, 1897–1907 (1995).
Peng, S. et al. In Barrett’s esophagus patients and Barrett’s cell lines, ursodeoxycholic acid increases antioxidant expression and prevents DNA damage by bile acids. Am. J. Physiol. Gastrointest. Liver Physiol. 307, G129–G139 (2014).
Huo, X. et al. Deoxycholic acid causes DNA damage while inducing apoptotic resistance through NF-kappaB activation in benign Barrett’s epithelial cells. Am. J. Physiol. Gastrointest. Liver Physiol. 301, G278–G286 (2011).
Abdel-Latif, M. M., Inoue, H. & Reynolds, J. V. Opposing effects of bile acids deoxycholic acid and ursodeoxycholic acid on signal transduction pathways in oesophageal cancer cells. Eur. J. Cancer Prev. 25, 368–379 (2016).
Jolly, A. J., Wild, C. P. & Hardie, L. J. Sodium deoxycholate causes nitric oxide mediated DNA damage in oesophageal cells. Free. Radic. Res. 43, 234–240 (2009).
Gambhir, S., Vyas, D., Hollis, M., Aekka, A. & Vyas, A. Nuclear factor kappa B role in inflammation associated gastrointestinal malignancies. World J. Gastroenterol. 21, 3174–3183 (2015).
Guan, B., Li, H., Yang, Z., Hoque, A. & Xu, X. Inhibition of farnesoid X receptor controls esophageal cancer cell growth in vitro and in nude mouse xenografts. Cancer 119, 1321–1329 (2013).
Camilleri, M. Bile acid diarrhea: prevalence, pathogenesis, and therapy. Gut Liver 9, 332–339 (2015).
Walters, J. R. & Appleby, R. N. A variant of FGF19 for treatment of disorders of cholestasis and bile acid metabolism. Ann. Transl. Med. 3, S7 (2015).
Walters, J. R. Bile acid diarrhoea and FGF19: new views on diagnosis, pathogenesis and therapy. Nat. Rev. Gastroenterol. Hepatol. 11, 426–434 (2014).
Oduyebo, I. et al. Effects of NGM282, an FGF19 variant, on colonic transit and bowel function in functional constipation: a randomized phase 2 trial. Am. J. Gastroenterol. 113, 725–734 (2018).
Camilleri, M. et al. Irritable bowel syndrome-diarrhea: characterization of genotype by exome sequencing, and phenotypes of bile acid synthesis and colonic transit. Am. J. Physiol. Gastrointest. Liver Physiol. 306, G13–G26 (2014).
Walters, J. R. et al. The response of patients with bile acid diarrhoea to the farnesoid X receptor agonist obeticholic acid. Aliment. Pharmacol. Ther. 41, 54–64 (2015).
Mroz, M. S. et al. Farnesoid X receptor agonists attenuate colonic epithelial secretory function and prevent experimental diarrhoea in vivo. Gut 63, 808–817 (2014).
Lefebvre, P., Cariou, B., Lien, F., Kuipers, F. & Staels, B. Role of bile acids and bile acid receptors in metabolic regulation. Physiol. Rev. 89, 147–191 (2009).
Wang, Y. M., Ong, S. S., Chai, S. C. & Chen, T. Role of CAR and PXR in xenobiotic sensing and metabolism. Expert Opin. Drug Metab. Toxicol. 8, 803–817 (2012).
Ihunnah, C. A., Jiang, M. & Xie, W. Nuclear receptor PXR, transcriptional circuits and metabolic relevance. Biochim. Biophys. Acta 1812, 956–963 (2011).
Wallace, K. et al. The PXR is a drug target for chronic inflammatory liver disease. J. Steroid Biochem. Mol. Biol. 120, 137–148 (2010).
D’Aldebert, E. et al. Bile salts control the antimicrobial peptide cathelicidin through nuclear receptors in the human biliary epithelium. Gastroenterology 136, 1435–1443 (2009).
Ivanov, I. I. et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126, 1121–1133 (2006).
McMahan, R. H. et al. Bile acid receptor activation modulates hepatic monocyte activity and improves nonalcoholic fatty liver disease. J. Biol. Chem. 288, 11761–11770 (2013).
Li, T. et al. The G protein-coupled bile acid receptor, TGR5, stimulates gallbladder filling. Mol. Endocrinol. 25, 1066–1071 (2011).
Harach, T. et al. TGR5 potentiates GLP-1 secretion in response to anionic exchange resins. Sci. Rep. 2, 430 (2012).
Brighton, C. A. et al. Bile acids trigger GLP-1 release predominantly by accessing basolaterally located G protein-coupled bile acid receptors. Endocrinology 156, 3961–3970 (2015).
Chiang, J. Y. Sphingosine-1-phosphate receptor 2: a novel bile acid receptor and regulator of hepatic lipid metabolism? Hepatology 61, 1118–1120 (2015).
Beuers, U., Trauner, M., Jansen, P. & Poupon, R. New paradigms in the treatment of hepatic cholestasis: from UDCA to FXR, PXR and beyond. J. Hepatol. 62, S25–S37 (2015).
Beuers, U. et al. The biliary HCO3− umbrella: a unifying hypothesis on pathogenetic and therapeutic aspects of fibrosing cholangiopathies. Hepatology 52, 1489–1496 (2010).
Goodwin, B. et al. A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Mol. Cell 6, 517–526 (2000).
Ananthanarayanan, M., Balasubramanian, N., Makishima, M., Mangelsdorf, D. J. & Suchy, F. J. Human bile salt export pump promoter is transactivated by the farnesoid X receptor/bile acid receptor. J. Biol. Chem. 276, 28857–28865 (2001).
Huang, L. et al. Farnesoid X receptor activates transcription of the phospholipid pump MDR3. J. Biol. Chem. 278, 51085–51090 (2003).
Baghdasaryan, A. et al. Dual farnesoid X receptor/TGR5 agonist INT-767 reduces liver injury in the Mdr2−/− (Abcb4−/−) mouse cholangiopathy model by promoting biliary HCO3− output. Hepatology 54, 1303–1312 (2011).
Hirschfield, G. M. et al. Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. Gastroenterology 148, 751–761 e758 (2015).
Nevens, F. et al. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N. Engl. J. Med. 375, 631–643 (2016).
Trauner, M. et al. Long-term efficacy and safety of obeticholic acid for patients with primary biliary cholangitis: 3-year results of an international open-label extension study. Lancet Gastroenterol. Hepatol. 4, 445–453 (2019).
Kowdley, K. V. et al. A randomized trial of obeticholic acid monotherapy in patients with primary biliary cholangitis. Hepatology 67, 1890–1902 (2018).
Younossi, Z. M. et al. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial. Lancet 394, 2184–2196 (2019).
Kowdley, K. V. et al. A randomized, placebo-controlled, phase II study of obeticholic acid for primary sclerosing cholangitis. J. Hepatol. 73, 94–101 (2020).
Trauner, M. et al. The nonsteroidal farnesoid X receptor agonist cilofexor (GS-9674) improves markers of cholestasis and liver injury in patients with primary sclerosing cholangitis. Hepatology 70, 788–801 (2019).
Kowdley, K. V. M. G., Pagadala, M. R., Gulamhusein, A., Swain, M. G. & Neff, G. W. The nonsteroidal farnesoid x receptor (FXR) agonist cilofexor improves liver biochemistry in patients with primary biliary cholangitis (PBC): a phase 2, randomized, placebo-controlled trial. Hepatology 70, 2 (2019).
Mayo, M. J. et al. NGM282 for treatment of patients with primary biliary cholangitis: a multicenter, randomized, double-blind, placebo-controlled trial. Hepatol. Commun. 2, 1037–1050 (2018).
Hirschfield, G. M. et al. Effect of NGM282, an FGF19 analogue, in primary sclerosing cholangitis: a multicenter, randomized, double-blind, placebo-controlled phase II trial. J. Hepatol. 70, 483–493 (2019).
Duboc, H., Tache, Y. & Hofmann, A. F. The bile acid TGR5 membrane receptor: from basic research to clinical application. Dig. Liver Dis. 46, 302–312 (2014).
Trauner, M., Fuchs, C. D., Halilbasic, E. & Paumgartner, G. New therapeutic concepts in bile acid transport and signaling for management of cholestasis. Hepatology 65, 1393–1404 (2017).
Miethke, A. G. et al. Pharmacological inhibition of apical sodium-dependent bile acid transporter changes bile composition and blocks progression of sclerosing cholangitis in multidrug resistance 2 knockout mice. Hepatology 63, 512–523 (2016).
Baghdasaryan, A. et al. Inhibition of intestinal bile acid absorption improves cholestatic liver and bile duct injury in a mouse model of sclerosing cholangitis. J. Hepatol. 64, 674–681 (2016).
Hegade, V. S. et al. Effect of ileal bile acid transporter inhibitor GSK2330672 on pruritus in primary biliary cholangitis: a double-blind, randomised, placebo-controlled, crossover, phase 2a study. Lancet 389, 1114–1123 (2017).
Mayo, M. J. et al. A randomized, controlled, phase 2 study of Maralixibat in the treatment of itching associated with primary biliary cholangitis. Hepatol. Commun. 3, 365–381 (2019).
Al-Dury, S. & Marschall, H. U. Ileal bile acid transporter inhibition for the treatment of chronic constipation, cholestatic pruritus, and NASH. Front. Pharmacol. 9, 931 (2018).
Karpen, S. J., Kelly, D., Mack, C. & Stein, P. Ileal bile acid transporter inhibition as an anticholestatic therapeutic target in biliary atresia and other cholestatic disorders. Hepatol. Int. 14, 677–689 (2020).
Yoon, Y. B. et al. Effect of side-chain shortening on the physiologic properties of bile acids: hepatic transport and effect on biliary secretion of 23-nor-ursodeoxycholate in rodents. Gastroenterology 90, 837–852 (1986).
Fickert, P. et al. norUrsodeoxycholic acid improves cholestasis in primary sclerosing cholangitis. J. Hepatol. 67, 549–558 (2017).
Ozcan, U. et al. Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science 313, 1137–1140 (2006).
Makishima, M. et al. Vitamin D receptor as an intestinal bile acid sensor. Science 296, 1313–1316 (2002).
Marschall, H. U. et al. Combined rifampicin and ursodeoxycholic acid treatment does not amplify rifampicin effects on hepatic detoxification and transport systems in humans. Digestion 86, 244–249 (2012).
Lindor, K. D. et al. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology 39, 770–778 (2004).
Leuschner, U. F. et al. High-dose ursodeoxycholic acid therapy for nonalcoholic steatohepatitis: a double-blind, randomized, placebo-controlled trial. Hepatology 52, 472–479 (2010).
Ratziu, V. et al. A randomized controlled trial of high-dose ursodesoxycholic acid for nonalcoholic steatohepatitis. J. Hepatol. 54, 1011–1019 (2011).
Kars, M. et al. Tauroursodeoxycholic acid may improve liver and muscle but not adipose tissue insulin sensitivity in obese men and women. Diabetes 59, 1899–1905 (2010).
Ding, L., Yang, L., Wang, Z. & Huang, W. Bile acid nuclear receptor FXR and digestive system diseases. Acta Pharm. Sin. B 5, 135–144 (2015).
Neuschwander-Tetri, B. A. et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 385, 956–965 (2015).
Patel, K. et al. Cilofexor, a nonsteroidal FXR agonist, in non-cirrhotic patients with nonalcoholic steatohepatitis: a phase 2 randomized controlled trial. Hepatology 72, 58–71 (2020).
Loomba, R. et al. Combination therapies including cilofexor and firsocostat for bridging fibrosis and cirrhosis due to NASH. Hepatology 73, 625–643 (2021).
Lucas, K. J. Tropifexor, a highly potent FXR agonist, produces robust and dose-dependent reductions in hepatic fat and serum alanine aminotransferase in patients with fibrotic NASH after 12 weeks of therapy: FLIGHT-FXR Part C interim results. Dig. Liver Dis. 52, e38 (2020).
Cicione, C., Degirolamo, C. & Moschetta, A. Emerging role of fibroblast growth factors 15/19 and 21 as metabolic integrators in the liver. Hepatology 56, 2404–2411 (2012).
Harrison, S. A. et al. Efficacy and safety of Aldafermin, an engineered FGF19 Analog, in a randomized, double-blind, placebo-controlled trial of patients with nonalcoholic steatohepatitis. Gastroenterology 160, 219–231.e1 (2021).
Harrison, S. A. et al. NGM282 for treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 391, 1174–1185 (2018).
Harrison, S. A. et al. NGM282 improves liver fibrosis and histology in 12 weeks in patients with nonalcoholic steatohepatitis. Hepatology 71, 1198–1212 (2020).
Rinella, M. E. et al. Rosuvastatin improves the FGF19 analogue NGM282-associated lipid changes in patients with non-alcoholic steatohepatitis. J. Hepatol. 70, 735–744 (2019).
Loomba, R. et al. The commensal microbe veillonella as a marker for response to an FGF19 analog in NASH. Hepatology 73, 126–143 (2021).
Trauner, M. et al. Potential of nor-ursodeoxycholic acid in cholestatic and metabolic disorders. Dig. Dis. 33, 433–439 (2015).
Ridlon, J. M., Kang, D. J. & Hylemon, P. B. Bile salt biotransformations by human intestinal bacteria. J. Lipid Res. 47, 241–259 (2006).
Parseus, A. et al. Microbiota-induced obesity requires farnesoid X receptor. Gut 66, 429–437 (2017).
Ilan, Y. Leaky gut and the liver: a role for bacterial translocation in nonalcoholic steatohepatitis. World J. Gastroenterol. 18, 2609–2618 (2012).
Wigg, A. J. et al. The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumour necrosis factor alpha in the pathogenesis of non-alcoholic steatohepatitis. Gut 48, 206–211 (2001).
Wyke, R. J. Problems of bacterial infection in patients with liver disease. Gut 28, 623–641 (1987).
Clements, W. D. et al. Role of the gut in the pathophysiology of extrahepatic biliary obstruction. Gut 39, 587–593 (1996).
Hackstein, C. P. et al. Gut microbial translocation corrupts myeloid cell function to control bacterial infection during liver cirrhosis. Gut 66, 507–518 (2017).
Fouts, D. E., Torralba, M., Nelson, K. E., Brenner, D. A. & Schnabl, B. Bacterial translocation and changes in the intestinal microbiome in mouse models of liver disease. J. Hepatol. 56, 1283–1292 (2012).
Maillette de Buy Wenniger, L. & Beuers, U. Bile salts and cholestasis. Dig. Liver Dis. 42, 409–418 (2010).
Hegade, V. S., Speight, R. A., Etherington, R. E. & Jones, D. E. Novel bile acid therapeutics for the treatment of chronic liver diseases. Ther. Adv. Gastroenterol. 9, 376–391 (2016).
Lorenzo-Zuniga, V. et al. Oral bile acids reduce bacterial overgrowth, bacterial translocation, and endotoxemia in cirrhotic rats. Hepatology 37, 551–557 (2003).
Hofmann, A. F. & Eckmann, L. How bile acids confer gut mucosal protection against bacteria. Proc. Natl Acad. Sci. USA 103, 4333–4334 (2006).
Romagnani, S. T-cell subsets (Th1 versus Th2). Ann. Allergy Asthma Immunol. 85, 9–18 (2000).
Schnappauf, O., Chae, J. J., Kastner, D. L. & Aksentijevich, I. The pyrin inflammasome in health and disease. Front. Immunol. 10, 1745 (2019).
Kohli, R. et al. Bile acid signaling: mechanism for bariatric surgery, cure for NASH? Dig. Dis. 33, 440–446 (2015).
Ryan, K. K. et al. FXR is a molecular target for the effects of vertical sleeve gastrectomy. Nature 509, 183–188 (2014).
Manning, S., Pucci, A. & Batterham, R. L. GLP-1: a mediator of the beneficial metabolic effects of bariatric surgery? Physiology 30, 50–62 (2015).
Nakatani, H. et al. Serum bile acid along with plasma incretins and serum high-molecular weight adiponectin levels are increased after bariatric surgery. Metabolism 58, 1400–1407 (2009).
Tremaroli, V. et al. Roux-en-Y gastric bypass and vertical banded gastroplasty induce long-term changes on the human gut microbiome contributing to fat mass regulation. Cell Metab. 22, 228–238 (2015).
Acknowledgements
M.T. is supported by grants I2755-B30 and F7310-B21 from the Austrian Science Foundation.
Author information
Authors and Affiliations
Contributions
M.T. conceptualized the article, and reviewed and edited the manuscript before submission. C.D.F. wrote the article.
Corresponding author
Ethics declarations
Competing interests
M.T. discloses that he has served as speaker for Falk Foundation, Gilead, Intercept and MSD; he has advised for Albireo, BiomX, Boehringer Ingelheim, Falk Pharma GmbH, Genfit, Gilead, Intercept, Janssen, MSD, Novartis, Phenex, Regulus and Shire. He further received travel grants from Abbvie, Falk Pharma GmbH, Gilead, and Intercept and research grants from Albireo, Alnylam, Cymabay, Falk, Gilead, Intercept, MSD Takeda and UltraGenyx. He is also co-inventor of patents on the medical use of NorUDCA filed by the Medical Universities of Graz and Vienna. C.D.F. received travel grants from Gilead, Falk Pharma GmbH and Abbvie.
Additional information
Peer review information
Nature Reviews Gastroenterology & Hepatology thanks Kiran Koelfat, who co-reviewed with Frank Schaap; John Chiang; and Jose Marin for their contribution to the peer review of this work.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Fuchs, C.D., Trauner, M. Role of bile acids and their receptors in gastrointestinal and hepatic pathophysiology. Nat Rev Gastroenterol Hepatol 19, 432–450 (2022). https://doi.org/10.1038/s41575-021-00566-7
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41575-021-00566-7
- Springer Nature Limited
This article is cited by
-
The gut-liver axis in hepatobiliary diseases
Inflammation and Regeneration (2024)
-
Another renaissance for bile acid gastrointestinal microbiology
Nature Reviews Gastroenterology & Hepatology (2024)
-
Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases
Signal Transduction and Targeted Therapy (2024)
-
FXR-FGF19 signaling in the gut–liver axis is dysregulated in patients with cirrhosis and correlates with impaired intestinal defence
Hepatology International (2024)
-
Gastric intestinal metaplasia: progress and remaining challenges
Journal of Gastroenterology (2024)